Skip to content
2000
image of Interleukin-10 Promotes Treg Formation and Tumorigenesis via Regulating Nrp-1/PDX1/FoxP3 Axis: Insights from Integrative Data Analysis

Abstract

Introduction

This study aimed to explore the mechanisms by which interleukin-10 (IL-10) influences tumorigenesis through T regulatory cells (Treg) regulation.

Background

Environmental factors, such as IL-10, significantly shape the immune microenvironment and tumor progression, yet the regulatory pathways remain unclear.

Objective

1) To elucidate the regulatory mechanism of IL-10 on Treg cells through assays; 2) To elaborate whether Nrp-1/PDX1 knockout affects tumorigenesis assays.

Methods

CD4+ T cells were isolated from the healthy mice's spleen and induced to differentiate into Treg cells. Then, after being treated with IL-10 and mouse melanoma cell supernatant (CM), the expression levels of Nrp-1 and FoxP3 in Treg cells were examined qRT-PCR and Western blotting. The ratio of Treg cells was measured by flow cytometry. The interaction between Nrp-1 and PDX1 proteins was detected through GST pull-down assay, Co-IP, Western blotting and immunofluorescence staining. STAT3 luciferase activity was detected, and the expression levels of JAK1 and STAT1 proteins were detected by Western blotting. Furthermore, the B16-bearing melanoma mice and Nrp-1/PDX1 knockout mice model were established to verify the effects of Nrp-1 and PDX1 on Treg formation and tumor development.

Results

The results demonstrated that IL-10 promoted Nrp-1 expression in Treg cells the JAK-STAT3 signaling pathway. Nrp-1 could combine with PDX1 to form a complex, facilitating PDX1-mediated activation of FoxP3 and Treg production. In melanoma xenograft models, targeting Nrp-1 and PDX1 using shRNAs or antibodies significantly reduced Treg levels and inhibited tumor growth. Collectively, IL-10 promotes Treg formation and tumorigenesis regulating Nrp-1/PDX1/FoxP3 axis.

Discussion

This study was the first to identify the interaction between Nrp-1 and PDX1, leading to PDX1 ubiquitination, which enhanced FoxP3 expression and Treg function in the tumor microenvironment. These novel insights highlighted the Nrp-1/PDX1/FoxP3 axis as a critical regulator of Treg-mediated tumorigenesis, offering potential targets for cancer therapy.

Conclusion

These findings highlight the interplay between environmental influences and immune regulation, providing novel insights into Treg-mediated tumorigenesis and suggesting potential strategies for targeted therapy.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/ctmc/10.2174/0115680266401850250927084313
2025-10-10
2025-11-08

  • From This Site

    /content/journals/ctmc/10.2174/0115680266401850250927084313
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Butera A. Sanchez M. Pronio A. Amendola A. De Nitto D. Di Carlo N. Lande R. Frasca L. Borrini F. Pica R. Boirivant M. CD3+CD4+LAP+Foxp3-regulatory cells of the colonic lamina propria limit disease extension in ulcerative colitis. Front. Immunol. 2018 9 2511 10.3389/fimmu.2018.02511 30425718
    [Google Scholar]
  2. Li Y. Wang Z. Lin H. Wang L. Chen X. Liu Q. Zuo Q. Hu J. Wang H. Guo J. Xie L. Tang J. Li Z. Hu L. Xu L. Zhou X. Ye L. Huang Q. Xu L. Bcl6 preserves the suppressive function of regulatory t cells during tumorigenesis. Front. Immunol. 2020 11 806 10.3389/fimmu.2020.00806 32477338
    [Google Scholar]
  3. Gao Y. Yao Y. Zhang X. Chen F. Meng X. Chen X. Wang C. Liu Y. Tian X. Shou S. Chai Y. Regulatory T cells: Angels or demons in the pathophysiology of sepsis? Front. Immunol. 2022 13 829210 10.3389/fimmu.2022.829210 35281010
    [Google Scholar]
  4. Shiri A.M. Zhang T. Bedke T. Zazara D.E. Zhao L. Lücke J. Sabihi M. Fazio A. Zhang S. Tauriello D.V.F. Batlle E. Steglich B. Kempski J. Agalioti T. Nawrocki M. Xu Y. Riecken K. Liebold I. Brockmann L. Konczalla L. Bosurgi L. Mercanoglu B. Seeger P. Küsters N. Lykoudis P.M. Heumann A. Arck P.C. Fehse B. Busch P. Grotelüschen R. Mann O. Izbicki J.R. Hackert T. Flavell R.A. Gagliani N. Giannou A.D. Huber S. IL-10 dampens antitumor immunity and promotes liver metastasis via PD-L1 induction. J. Hepatol. 2024 80 4 634 644 10.1016/j.jhep.2023.12.015 38160941
    [Google Scholar]
  5. Murai M. Turovskaya O. Kim G. Madan R. Karp C.L. Cheroutre H. Kronenberg M. Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. Nat. Immunol. 2009 10 11 1178 1184 10.1038/ni.1791 19783988
    [Google Scholar]
  6. Zhao P.Y. Wang Y.Q. Liu X.H. Zhu Y.J. Zhao H. Zhang Q.X. Qi F. Li J.L. Zhang N. Fan Y.P. Li K.N. Zhao Y.Y. Lei J.F. Wang L. Bu Shen Yi Sui capsule promotes remyelination correlating with Sema3A/NRP-1, LIF/LIFR and Nkx6.2 in mice with experimental autoimmune encephalomyelitis. J. Ethnopharmacol. 2018 217 36 48 10.1016/j.jep.2018.02.014 29428242
    [Google Scholar]
  7. Hossain M.G. Akter S. Uddin M.J. Emerging role of neuropilin-1 and angiotensin-converting enzyme-2 in renal carcinoma-associated COVID-19 pathogenesis. Infect. Dis. Rep. 2021 13 4 902 909 10.3390/idr13040081 34698182
    [Google Scholar]
  8. Yoshimura R. Kyuka A. Jinno M. Nishio S. Matsusaka M. Nishida T. Endo Y. Increase in neuropilin-1 on the surface of growth cones and putative raft domains in neuronal NG108-15 cells co-cultured with vascular smooth muscle SM-3 cells. J. Membr. Biol. 2015 248 2 171 178 10.1007/s00232‑014‑9754‑9 25416424
    [Google Scholar]
  9. Saleki K. Banazadeh M. Miri N.S. Azadmehr A. Triangle of cytokine storm, central nervous system involvement, and viral infection in COVID-19: The role of sFasL and neuropilin-1. Rev. Neurosci. 2022 33 2 147 160 10.1515/revneuro‑2021‑0047 34225390
    [Google Scholar]
  10. Chuckran C.A. Liu C. Bruno T.C. Workman C.J. Vignali D.A.A. Neuropilin-1: A checkpoint target with unique implications for cancer immunology and immunotherapy. J. Immunother. Cancer 2020 8 2 000967 10.1136/jitc‑2020‑000967 32675311
    [Google Scholar]
  11. Papatriantafyllou M. Neuropilin 1 — distinguishing TReg cell subsets. Nat. Rev. Immunol. 2012 12 11 746 747 10.1038/nri3323
    [Google Scholar]
  12. Sidaway P. Immunotherapy: Neuropilin-1 is required for Treg stability. Nat. Rev. Clin. Oncol. 2017 14 8 458 458 28607516
    [Google Scholar]
  13. Nova-Lamperti E. Huber S. Amsen D. Chen W. Zheng S.G. Lin J. Neuropilin 1 identifies a new subpopulation of tgf β induced foxp3+ regulatory t cells with potent suppressive function and enhanced stability during inflammation. Front. Immunol. 2022 ••• 13 10.3389/fimmu.2022.900139
    [Google Scholar]
  14. Abberger H. Hose M. Ninnemann A. Menne C. Eilbrecht M. Lang K.S. Matuschewski K. Geffers R. Herz J. Buer J. Westendorf A.M. Hansen W. Neuropilin-1 identifies a subset of highly activated CD8+ T cells during parasitic and viral infections. PLoS Pathog. 2023 19 11 1011837 10.1371/journal.ppat.1011837 38019895
    [Google Scholar]
  15. Chaudhary B. Khaled Y.S. Ammori B.J. Elkord E. Neuropilin 1: Function and therapeutic potential in cancer. Cancer Immunol. Immunother. 2014 63 2 81 99 10.1007/s00262‑013‑1500‑0 24263240
    [Google Scholar]
  16. Gooraninejad S. Hoveizi E. Hushmandi K. Gooraninejad S. Tabatabaei S.R.F. Small molecule differentiate PDX1-expressing cells derived from human endometrial stem cells on PAN electrospun nanofibrous scaffold: Applications for the treatment of diabetes in rat. Mol. Neurobiol. 2020 57 9 3969 3978 10.1007/s12035‑020‑02007‑z 32632606
    [Google Scholar]
  17. Su Y. Li J. Chen L. Lian H. Qie Y. PDX1 methylation, NGN3 and Pax6 expression levels in pregnant women with gestational diabetes mellitus and their association with neonatal blood sugars and birth weight. Pak. J. Med. Sci. 2024 40 3Part-II 509 513 38356808
    [Google Scholar]
  18. Sakai H. Eishi Y. Li X.L. Akiyama Y. Miyake S. Takizawa T. Konishi N. Tatematsu M. Koike M. Yuasa Y. PDX1 homeobox protein expression in pseudopyloric glands and gastric carcinomas. Gut 2004 53 3 323 330 10.1136/gut.2003.026609 14960508
    [Google Scholar]
  19. Yang W. Chi Y. Meng Y. Chen Z. Xiang R. Yan H. Yang J. FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells. FASEB J. 2020 34 3 3915 3931 10.1096/fj.201902368RR 31944392
    [Google Scholar]
  20. Amatya C. Radichev I.A. Ellefson J. Williams M. Savinov A.Y. Self transducible bimodal pdx1 foxp3 protein lifts insulin secretion and curbs autoimmunity, boosting tregs in type1 diabetic mice. Mol. Ther. 2018 26 1 184 198 10.1016/j.ymthe.2017.08.014
    [Google Scholar]
  21. Mizuhashi S. Kubo Y. Fukushima S. Kanemaru H. Nakahara S. Miyasita A. Ishibashi T. Kuriyama H. Kimura T. Masuguchi S. Zhang R. Iwama T. Nakatsura T. Uemura Y. Senju S. Ihn H. Immune cell therapy against disseminated melanoma by utilizing induced pluripotent stem cell-derived myeloid cell lines producing interferon-beta or interleukin-15/interleukin-15 receptor alpha. J. Dermatol. Sci. 2021 102 2 133 136 10.1016/j.jdermsci.2021.03.005 33836927
    [Google Scholar]
  22. Wang J. Wang Z. Yuan J. Wang Q. Shen X. Upregulation of miR-137 expression suppresses tumor growth and progression via interacting with DNMT3a through inhibiting the PTEN/Akt signaling in HCC. OncoTargets Ther. 2021 14 165 176 10.2147/OTT.S268570 33447058
    [Google Scholar]
  23. Zeng X. Tang X. Chen X. Wen H. RNF182 induces p65 ubiquitination to affect PDL1 transcription and suppress immune evasion in lung adenocarcinoma. Immun. Inflamm. Dis. 2023 11 5 864 10.1002/iid3.864 37249301
    [Google Scholar]
  24. Gnanasekaran P. Pappu H.R. Detection of protein–protein interactions using glutathione-s-transferase (GST) pull-down assay technique. Methods Mol. Biol. 2023 2690 111 115 10.1007/978‑1‑0716‑3327‑4_10 37450141
    [Google Scholar]
  25. Vardaka P. Lozano T. Bot C. Ellery J. Whiteside S.K. Imianowski C.J. Farrow S. Walker S. Okkenhaug H. Yang J. Okkenhaug K. Kuo P. Roychoudhuri R. A cell-based bioluminescence assay reveals dose-dependent and contextual repression of AP-1-driven gene expression by BACH2. Sci. Rep. 2020 10 1 18902 10.1038/s41598‑020‑75732‑z 33144667
    [Google Scholar]
  26. Zhao Y. Luan H. Jiang H. Xu Y. Wu X. Zhang Y. Li R. Gegen Qinlian decoction relieved DSS-induced ulcerative colitis in mice by modulating Th17/Treg cell homeostasis via suppressing IL-6/JAK2/STAT3 signaling. Phytomedicine 2021 84 153519 10.1016/j.phymed.2021.153519 33640781
    [Google Scholar]
  27. Li Y. Wang Z. Xu H. Hong Y. Shi M. Hu B. Wang X. Ma S. Wang M. Cao C. Zhu H. Hu D. Xu C. Lin Y. Xu G. Yao Y. Zeng R. Targeting the transmembrane cytokine co-receptor neuropilin-1 in distal tubules improves renal injury and fibrosis. Nat. Commun. 2024 15 1 5731 10.1038/s41467‑024‑50121‑6 38977708
    [Google Scholar]
  28. Wang S. Gao X. Shen G. Wang W. Li J. Zhao J. Wei Y.Q. Edwards C.K. Interleukin-10 deficiency impairs regulatory T cell-derived neuropilin-1 functions and promotes Th1 and Th17 immunity. Sci. Rep. 2016 6 1 24249 10.1038/srep24249 27075020
    [Google Scholar]
  29. Wang Y. Li J. Nakahata S. Iha H. Complex role of regulatory T cells (Tregs) in the tumor microenvironment: Their molecular mechanisms and bidirectional effects on cancer progression. Int. J. Mol. Sci. 2024 25 13 7346 10.3390/ijms25137346 39000453
    [Google Scholar]
  30. Elemam N.M. Mekky R.Y. Rashid G. Braoudaki M. Youness R.A. Pharmacogenomic and epigenomic approaches to untangle the enigma of IL-10 blockade in oncology. Expert Rev. Mol. Med. 2024 26 1 10.1017/erm.2023.26 38186186
    [Google Scholar]
  31. Gong X.P. Tang Y. Song Y.Y. Du G. Li J. Comprehensive review of phytochemical constituents, pharmacological properties, and clinical applications of Prunus mume. Front. Pharmacol. 2021 12 679378 10.3389/fphar.2021.679378 34122104
    [Google Scholar]
  32. Zhang S. Gan X. Qiu J. Ju Z. Gao J. Zhou J. Shi C. Zhu Y. Li Z. IL-10 derived from Hepatocarcinoma cells improves human induced regulatory T cells function via JAK1/STAT5 pathway in tumor microenvironment. Mol. Immunol. 2021 133 163 172 10.1016/j.molimm.2021.02.014 33667986
    [Google Scholar]
/content/journals/ctmc/10.2174/0115680266401850250927084313
Loading
Interleukin-10 Promotes Treg Formation and Tumorigenesis via Regulating Nrp-1/PDX1/FoxP3 Axis: Insights from Integrative Data Analysis
Bentham Science Publishers ; https://doi.org/10.2174/0115680266401850250927084313
/content/journals/ctmc/10.2174/0115680266401850250927084313
/content/journals/ctmc/10.2174/0115680266401850250927084313
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: PDX1 ; Cancer development ; Treg ; Nrp-1 ; FoxP3 ; IL-10

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test